Abnormal ovarian conditions include cancer, autoimmunity, and premature ovarian failure. Infertility is one of the clinical manifestations.
Ovarian cancer is the leading cause of gynecologic cancer death in the developed world largely because there is no effective screening method, and symptoms occur late in the progression of the disease. New biomarkers are needed if screening is to have an impact on outcomes of females with ovarian cancer and/or ovarian autoimmunity. Because ovarian cells cannot be readily obtained from the female genital tract, a screening method based on the analysis of serum biomarkers is highly desired.
Strong evidence exists for an autoimmune disease of the ovary, but no corresponding, standardized commercial test is available for its clinical diagnosis. The disease is associated with specific anti-ovarian antibodies. Ovarian autoimmune disease occurs in but is not limited to women with infertility and in women with premature menopause. Not all women attempt to have children. Infertility is defined as the inability to conceive. Premature menopause (Premature Ovarian Failure, POF) is defined as cessation of menstruation before age 40. Based on extensive epidemiologic studies women who have never given birth are at are at high risk for ovarian cancer and would also benefit from antibody screening.
Ovarian function is assessed by evaluation of menstrual cycle patterns, cycle length, and measurement of early follicular phase FSH and estradiol. Early changes associated with ovarian failure, such as infertility or minor elevations of FSH (above 10 mIU/ml) may be subtle. Later changes may include more obvious disturbances, such as menstrual cycle changes, and elevations of FSH (above 40 mIU/ml). Although these changes are normal as a woman approaches menopause around age 50, the same changes in young women may signal a pathological process. However, endocrine tests do not differentiate between endocrine and autoimmune etiologies for ovarian dysfunction. Current hormone treatment of ovarian dysfunction may be less successful in the face of ovarian autoimmune disease.
Previously, the only method available for ovarian autoantibody detection was immunohistochemistry, and a prototype immunoassay test. Unfortunately immunohistochemical methods are subjective, labor intensive, qualitative, and—particularly with the ovary—are subject to significant variations in antigen content between tissue sections. The prototype ovarian antibody test was based on use of a microsomal fraction of the ovary in an ELISA format. The specific antigens reacting with patient sera were not identified in the prototype test. An improvement over this nonspecific ovarian antibody test is the test described in U.S. Pat. No. 6,458,550 and incorporated herein by reference. This assay was developed to test for autoimmunity by using autoantibodies to CYP17.
Antibodies to CYP17 are more common in patients with concomitant endocrine autoimmunity involving the adrenal (polyendocrine autoimmunity type 1 and 2) and do not detect all patients with ovarian autoimmunity.
Although it is less common than other gynecologic cancers, ovarian cancer mortality represents 2.5% of cancer deaths in the United States. This reflects a lack of early detection methods, because less than 25% of ovarian tumors are detected at Stage I. The five-year survival of patients with stage I/II ovarian tumors (80-90%) is dramatically higher than patients who are diagnosed with stage IV tumors (less than 30%). Improved survival rates result from early detection for prostate cancer (PSA test), breast cancer (mammography) and cervical cancer (PAP smear), thus earlier detection of ovarian tumors will significantly increase survival.
Despite reports describing tumor markers, there is currently no reliable diagnostic or screening test for ovarian cancer. Ovarian cancer does not usually cause symptoms at first. Many women have some symptoms, such as gas or pain or swelling in the abdomen, in the 6 to 12 months before ovarian cancer is found. Other symptoms are diarrhea or constipation, or an upset stomach. These symptoms are general and are more likely to be attributed to other causes. Usually, the cancer has spread by the time it is found. Currently, if ovarian cancer is suspected due to a pelvic mass during a pelvic exam, exploratory surgery is performed.
There is a plethora of putative protein markers reported for ovarian cancer, CA-125 being the most well known. CA-125, however, has poor specificity and predictive value for ovarian cancer detection, since it increases in endometriosis and during the normal menstrual cycle, and in the presence of other cancers. Among many non-specific markers identified in association with ovarian cancer, two have been described that appear to be relatively specific for ovarian cancer; mesothelin and HE4. However, this association was demonstrated only for relatively advanced stage ovarian cancer, making these markers less useful for predicting the onset of ovarian cancer at an early stage.
The biological activity of selenium (Se) has been studied for over 40 years and is now recognized as an essential trace element in eukaryotes and as a potent anticarcinogenic agent. Dietary Se affords protection against both the initiation and promotion of carcinogenesis, and there is increasing epidemiological evidence to support its anticarcinogenic role in humans. Se-binding proteins from various species including human have been identified and characterized. Some of them belong to a family of highly homologous cytosolic proteins with similar molecular weights (ca. 54-58 kDa) and overlapping tissue distributions in the kidney, liver, lung, gastrointestinal tract, and male and female endocrine glands. Se-binding proteins have been implicated in cellular growth control and protection from carcinogenesis and cancer.
Epidemiologic data indicates that women with infertility have a higher risk for ovarian and other cancers than women in the general population or women without infertility. There is no test to determine which patients have a higher risk for ovarian cancer or have very early tumors and would benefit from closer monitoring in order to detect ovarian cancer early when survival probability is highest.